Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors worldwide and understanding its underlying molecular mechanisms is crucial for the development of therapeutic strategies. The mitogen-activated protein kinase-kinase 3 (MKK3) is a specific activator of p38 MAP kinases (p38 MAPKs), which contributes to the regulation of several cellular functions, such as proliferation, differentiation, apoptosis as well as response to drugs. At present, the exact MKK3/p38 MAPK pathway contribution in cancer is heavily debated because of its pleiotropic function. In this work, we retrospectively explored the prognostic and pathobiologic relevance of MKK3 in a cohort of CRC patients and assessed MKK3 molecular functions in a panel of CRC lines and colonocytes primary cultures. We found increased MKK3 levels in late-stage CRC patients which correlated with shorter overall survival. Herein, we report that the MKK3 targeting by inducible RNA interference univocally exerts antitumor effects in CRC lines but not in primary colonocytes. While MKK3 depletion per se affects growth and survival by induction of sustained autophagy and death in some CRC lines, it potentiates response to chemotherapeutic drug 5-fluorouracil (5-FU) in all of the tested CRC lines in vitro. Here, we demonstrate for the first time that in CRC the MKK3 specifically activates p38delta MAPK isoform to sustain prosurvival signaling and that such effect is exacerbated upon 5-FU challenge. Indeed, p38delta MAPK silencing recapitulates MKK3 depletion effects in CRC cells in vitro and in vivo. Overall, our data identified a molecular mechanism through which MKK3 supports proliferation and survival signaling in CRC, further supporting MKK3 as a novel and extremely attractive therapeutic target for the development of promising strategies for the management of CRC patients.
Highlights
Colorectal cancer (CRC) is the third most common cancer, the fourth most common cause of cancer death, and the second most common cancer in terms of number of individuals living with cancer 5 years after diagnosis worldwide[1]
In accordance with p38 mitogen activated protein kinase (MAPK) involvement in many different cellular processes, it appears that mitogen-activated protein kinase-kinase 3 (MKK3) contribution to CRC tumor growth is manifold: we observed a cancer cell-line-specific dependence on MKK3, with autophagy being induced only in a subset of CRC lines upon MKK3 depletion, while this caused potentiation of 5-FU-induced killing in all of the tested CRC lines indicating that MKK3 inhibition exerts tumorsuppressive effects by affecting mechanisms other than autophagy induction
We demonstrated that in CRC p38delta MAPK is induced, and highly phosphorylated by MKK3 as a result of 5-FU exposure, indicating that, beyond p38 MAPK alpha-mediated induction of apoptosis, MKK3/p38delta MAPK pro-survival signaling is further triggered upon drug treatment
Summary
Colorectal cancer (CRC) is the third most common cancer, the fourth most common cause of cancer death, and the second most common cancer in terms of number of individuals living with cancer 5 years after diagnosis worldwide[1]. CRC is a complex disease with a variable and 73% in metastatic stage IV CRC patients undergoing potentially curative resections[2]. The mitogen-activated protein kinase-kinase 3 (MKK3) belongs to a dual specificity kinase group (MKK) and is activated by a wide array of upstream kinases (MEKK1–4) through Ser-189 and Thr-193 phosphorylation[3]. MKK3 serves, together with MKK6, as a specific activator of p38 mitogen activated protein kinase (MAPK)[4,5,6]. The p38 MAPK pathway is activated upon a variety of stimuli, including cytokines and growth factors, cellular
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